Medulloblastoma is the most common malignant brain tumor in children. Aggressive molecular subgroups have poorly understood biology and few targeted therapies. A high risk subgroup of SHH driven-tumors also shows amplification of the MYCN proto-oncogene, while 4 tumors demonstrate increased levels or amplification of MYCN. How can we target MYCN in medulloblastoma? We hypothesize that MYCN cooperates with the translational apparatus to drive transformation in medulloblastoma, and that inhibition of the mTOR kinase represents a critical therapeutic strategy for both MYCN/SHH co-driven, and Group 4 medulloblastoma. In both prostate and hematopoietic tumors, MYC drives tumorigenesis through interacting with the translational apparatus downstream of the mammalian target of rapamycin (mTOR) a master regulator of translation. The mTOR complex 1 (mTORC1) signals through Ribosomal Protein S6 kinase (S6K) and the translation initiation factor eIF4E. A new class of mTOR kinase inhibitors disrupts signaling through both mTORC1 effectors, whereas clinical allosteric binders (rapamycin and analogues) disrupt only S6K. These mechanistically distinct activities have enormous therapeutic implications, as in our Group 4 medulloblastoma model, mTOR kinase inhibitors, but not rapamycin, show efficacy. Importantly, we found cross-talk between MYCN and mTOR during medulloblastoma development. Our preliminary data point to a critical role for eIF4E in tumorigenesis at this nexus between MYCN and mTOR. These observations suggest that S6K is dispensable, whereas eIF4E is required for MYC/MYCN-driven medulloblastoma. In this proposal, we will determine how MYCN hijacks the translational apparatus for its oncogenic activity (A1). We recently developed distinct genetically engineered mouse (GEM) models for high-risk Group 4 and MYCN driven SHH-dependent medulloblastoma, in which mis-expression of MYCN drives oncogenesis. Using unique genetic approaches, we will separately evaluate the importance of S6K and eIF4E in our MYCN/SHH and Group 4 GEM models (A2). Finally, we will use clinical inhibitors of mTOR to evaluate S6K (allosteric inhibitors of mTOR) and eIF4E (mTOR kinase inhibitors) as therapeutic targets, analyzing cell lines, GEM models, and patient derived xenografts (PDX--A3). Successful completion elucidates fundamental targetable mechanisms in MYCN-driven medulloblastoma.

Public Health Relevance

Medulloblastoma is the most common malignant brain tumor in children. MYCN drives aggressive subtypes of medulloblastoma, but is undruggable. We explore interactions between MYCN and the translational apparatus in medulloblastoma, using both pharmacological and genetic approaches to elucidate fundamental targetable mechanisms in MYCN-driven medulloblastoma.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Fountain, Jane W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
An, Zhenyi; Aksoy, Ozlem; Zheng, Tina et al. (2018) Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene 37:1561-1575
Gwinn, Dana M; Lee, Alex G; Briones-Martin-Del-Campo, Marcela et al. (2018) Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase. Cancer Cell 33:91-107.e6
Fan, Qi Wen; Nicolaides, Theodore P; Weiss, William A (2018) Inhibiting 4EBP1 in Glioblastoma. Clin Cancer Res 24:14-21
Zheng, Tina; Ménard, Marie; Weiss, William A (2017) Neuroblastoma Metastases: Leveraging the Avian Neural Crest. Cancer Cell 32:395-397
Fan, QiWen; Aksoy, Ozlem; Wong, Robyn A et al. (2017) A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma. Cancer Cell 31:424-435
Cage, Tene Aneka; Chanthery, Yvan; Chesler, Louis et al. (2015) Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer. Front Oncol 5:111